title: Oxidation of polychlorinated biphenyls by liver tissue slices from phenobarbital-pretreated mice is congener-specific and atropselective.
abstract: Mouse models are powerful tools to study the developmental neurotoxicity of polychlorinated biphenyls (PCBs); however, studies of the oxidation of chiral PCB congeners to potentially neurotoxic hydroxylated metabolites (OH-PCBs) in mice have not been reported. Here, we investigate the atropselective oxidation of chiral PCB 91 (2,2',3,4',6-pentachlorobiphenyl), PCB 95 (2,2',3,5',6-pentachlorobiphenyl), PCB 132 (2,2',3,3',4,6'-hexachlorobiphenyl), PCB 136 (2,2',3,3',6,6'-hexachlorobiphenyl), and PCB 149 (2,2',3,4',5',6-hexachlorobiphenyl) to OH-PCBs in liver tissue slices prepared from female mice. The metabolite profile of PCB 136 typically followed the rank order 5-OH-PCB > 4-OH-PCB > 4,5-OH-PCB, and metabolite levels increased with PCB concentration and incubation time. A similar OH-PCB profile was observed with the other PCB congeners, with 5-OH-PCB/4-OH-PCB ratios ranging from 2 to 12. More 5-OH-PCB 136 was formed in liver tissue slices obtained from animals pretreated with phenobarbital (P450 2B inducer) or, to a lesser extent, dexamethasone (P450 2B and 3A enzyme inducer) compared to tissue slices prepared from vehicle-pretreated animals. The apparent rate of 5-OH-PCBs formation followed the approximate rank order PCB 149 > PCB 91 > PCB 132 ∼ PCB 136 > PCB 95. Atropselective gas chromatography revealed a congener-specific atropisomeric enrichment of major OH-PCB metabolites. Comparison of our results with published OH-PCB patterns and chiral signatures (i.e., the direction and extent of the atropisomeric enrichment) from rat liver microsomal revealed drastic differences between both species, especially following the induction of P450 2B enzymes. These species differences in the metabolism of chiral PCBs should be considered in developmental neurotoxicity studies of PCBs.
authors.affiliation: Department of Occupational and Environmental Health, College of Public Health and ‡Department of Pharmaceutical Sciences and Experimental Therapeutics, College of Pharmacy, The University of Iowa , Iowa City, Iowa 52242, United States.
authors.forename: Xianai
authors.initials: X
authors.lastname: Wu
authors.forename: Michael
authors.initials: M
authors.lastname: Duffel
authors.forename: Hans-Joachim
authors.initials: HJ
authors.lastname: Lehmler
mesh_terms: D000818:Animals; D003577:Cytochrome P-450 Enzyme System / Q000096:biosynthesis; D003907:Dexamethasone / Q000494:pharmacology; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008401:Gas Chromatography-Mass Spectrometry; D006801:Humans; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D008862:Microsomes, Liver / Q000378:metabolism; D010084:Oxidation-Reduction; D010634:Phenobarbital / Q000494:pharmacology*; D011078:Polychlorinated Biphenyls / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D051381:Rats; D013237:Stereoisomerism
chemical_list: D003907:Dexamethasone; D003577:Cytochrome P-450 Enzyme System; D011078:Polychlorinated Biphenyls; D010634:Phenobarbital